Paths of Progress Fall/Winter 2013

Hitching a Ride

Will an emerging cancer therapy that links potent drugs to tumor-seekers take the place of standard chemotherapy?by Elizabeth Dougherty

Eric Winer, MD (left), has been leading clinical trials at DF/BWCC focusing on the antibody-drug conjugate T-DM1.

Sarah Merchant was working as a Web designer in Boston when, at age 28, she was diagnosed with stage 4 metastatic breast cancer. Surgery, radiation, and a series of chemotherapy regimens followed, as did nerve damage, hair loss, and a general decline in her health.

Then Merchant heard about T-DM1, a trial drug promising the effectiveness of chemotherapy without the toxicity. "I wanted to get into that trial," she says.

T-DM1 is among the first of a new class of drugs called antibody-drug conjugates (ADCs). ADCs have the tumor-seeking smarts of monoclonal antibodies, but with an added punch. Powerful drugs hitch a ride with the antibody, allowing the ADC to deliver the drug directly to tumor cells. The tumor cell pulls the ADC inside, where enzymes break the tether, freeing the drug to destroy the cancer cell while leaving healthy cells unharmed.

ADCs build on the success of monoclonal antibodies, which seek out and destroy specific cells by recognizing antigens on the target cells' surface. The antigens act as flags that uniquely identify a type of cancer cell and wave the antibody in for a landing. For example, rituximab, the first monoclonal antibody therapy for cancer, approved in 1997, recognizes CD20, which is present on malignant B cells in non-Hodgkin lymphoma.

Smart as they are, antibodies don't achieve the ultimate goal of curing cancer, so attempts have been made to improve their tumor-destroying power. For some cancers, the answer has been combination therapy, such as chemoimmunotherapy, in which a monoclonal antibody such as rituximab is administered along with a systemic chemotherapy, such as CHOP, a four-drug chemo cocktail.

In the 1990s, Lee Nadler, MD, who is now senior vice president of experimental medicine at Dana-Farber, and colleagues tried to solve this problem by linking an antibody to a potent toxin, ricin, creating one of the first experimental immunotoxins. (Nadler had first identified CD20 as the target for rituximab.) The novel conjugate did not lead to an approved drug, "but that didn't stop people from trying," says Arnie Freedman, MD, clinical director of the Adult Lymphoma Program at Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC), who was a member of Nadler's team.

More than a decade later, in 2011, the FDA approved the first ADC, brentuximab vedotin, for relapsed and refractory Hodgkin lymphoma and a rare T cell lymphoma. In 2013, T-DM1 followed for metastatic breast cancer. Several other ADCs are in early stage testing for blood, ovarian, lung, and prostate cancers. With such rapid progress, it's tempting to think that ADCs — and their promises of fewer side effects and better results — will soon be the standard for cancer treatment. But a closer look reveals the work ahead.

Slow-motion Slam Dunk

In 2006, Ian Krop, MD, PhD, a breast oncologist also at the Susan F. Smith Center for Women's Cancers, began testing T-DM1. The ADC links a potent chemical toxin called DM1 to trastuzumab (Herceptin), an existing antibody therapeutic. Trastuzumab targets HER2, a flag seen in an aggressive form of breast cancer that tends to affect young women, like Merchant.

Two years ago, Merchant joined a T-DM1 clinical trial at DF/BWCC. After six months, her cancer had all but vanished. Since then, she's had no evidence of disease. Instead of living scan to scan, she now looks months ahead. "My quality of life has improved exponentially," she says. "My body has started to heal. My hair has come back. I feel like a person again."

Merchant's experience isn't unique. "It was very clear from the early studies in the metastatic setting that T-DM1 was going to be a winner," says Winer. "It doesn't work in everyone, but when it works, it works extraordinarily well."

Most likely, says Winer, T-DM1 is successful because HER2 is an outstanding target. Because HER2 is expressed much more prominently on cancer cells than other cells, the drug causes few side effects.

The earliest tests of T-DM1were so successful in women with advanced HER2-positive breast cancer that, by 2008, Krop and Winer were lobbying for trials with patients with earlier-stage disease. But instead of following this accelerated schedule, the drug spent five years proving itself in phase II and III trials. "T-DM1 was in so many ways a slam dunk," says Krop. "It should have been easy, but approval still took seven years."

Now, Winer and Krop can test it in patients with earlier stage disease. A trial for patients with high-risk cancer will test adding T-DM1 to the current standard therapy. A trial for patients with lower-risk disease will test T-DM1 instead of chemotherapy to see if it delivers the same effectiveness with less toxicity.

Obstacle Course

Meanwhile, brentuximab vedotin is showing "remarkable activity" against Hodgkin lymphoma and some other less common non-Hodgkin lymphomas, such as anaplastic large cell lymphoma, according to Freedman. Clinical trials are showing a 75 percent response rate in patients who were relapsing or not responding to other treatments.

Trials are now under way to test the drug in combination with existing therapies in patients with newly diagnosed disease. "We're trying to improve the initial cure rates so that patients are not subjected to more intensive and more toxic treatments if they relapse," says Eric Jacobsen, MD, an oncologist at DF/BWCC specializing in blood cancers.

Hodgkin lymphoma already has high cure rates and long remission times with standard chemotherapy, good things for patients but stumbling blocks when it comes to the introduction of new therapies. "If you have a therapy with an 88 percent cure rate, patients are understandably hesitant to try something new," says Jacobsen.

And for researchers investigating new drugs, long remission times, which are common in some lower grade non-Hodgkin lymphomas, mean longer waits for trial results, and, in turn, delays in approvals.

Another challenge, says Jacobsen, is that "these ADCs may not be as targeted as we think." Brentixumab vedotin's antibody targets CD30, a flag that appears on some types of lymphoma. In trials, however, the likelihood of responding to brentuximab vedotin did not correlate with the amount of CD30 found on the surface of the lymphoma cell. In fact, some patients who tested negative for CD30 had complete remission on the drug.

None of these hurdles are showstoppers. In fact, Freedman recently launched an early stage trial of an experimental ADC for lymphoma that targets CD37, another flag on malignant B cells. "Until we have extraordinarily high cure rates in all these diseases, there's always room for agents that have more specificity and less toxicity," says Freedman.

Twists and Turns

New ADCs are also in the works for ovarian, lung, and prostate cancer. A trial of the safety of an ADC for ovarian cancer showed signs of effectiveness in patients for whom all other treatments had failed. In this case, patients with higher levels of the drug's intended target, MUC16, fared better with the ADC. "These signals of activity are exciting because we potentially have a drug that would be effective in patients whose cancer is resistant to other therapies," says Joyce Liu, MD, MPH, a gynecologic oncologist at the Susan F. Smith Center for Women's Cancers who led DF/BWCC's participation in the trial.

Variations on ADCs are also in the works. Krop has begun an early study of a conjugate that links multiple HER2-targeted antibodies to a lipid bubble full of the chemotherapy drug doxorubicin. While T-DM1 links one antibody to just three or four molecules of DM1, this new approach scales up both the number of antibodies and the amount of drug, with the intent to improve both tumor-seeking and -destroying capabilities.

Excitement is building, but the real will become the way we treat cancer. For now, "there is a glimmer of hope that the ADCs we have so far are not going to be the only ones," says Krop. "With further improvements in technology and research, there may eventually be a wide spectrum of conjugates for different kinds of cancer."